While the role of mitochondrial dysfunction has been proposed in neurodegenerative diseases, the exact mechanism of mitochondrial pathogenesis is unclear. Our preliminary studies show that hormone receptors, estrogen receptors (ERs), and cAMP response elements binding protein (CREB) are present in the mitochondrial matrix of neurons. CREB directly binds to cAMP response elements (CREs) in the promoter regions (D-loop) of mitochondrial DNA. We also show that CREB is transcriptionally active in mitochondria and hypothesize that the regulation of mitochondrial gene expression by mitochondrial CREB may underlie some of the established protective effects in neuronal survival. This data implies that mitochondrial localization of ERs and CREB could be regulated by novel signaling pathways in the intact central nervous system and that their functions in the mitochondria might be important in neuronal survival. Therefore, we propose that the levels and activities of mitochondrial hormone receptors and transcription factors, which induce mitochondrial gene transactivation, may contribute to mitochondrial dysfunction and the subsequent neuronal loss observed in Huntington's disease (HD). Thus, the specific aims of our proposed study are: 1) To identify the topographic brain distribution of mitochondrial ERs and characterize mitochondrial estrogen receptor element (ERE) sites and interaction with CREB in neurons. 2) To determine the regulatory mechanism of mitochondrial ERs and CREB-mediated mitochondrial transcription. Protein Kinase A (PKA) is a well known enzyme for activation of ERs and phosphorylating CREB at Ser133. In this context, we propose that PKA localizes into the mitochondrial matrix and that mitochondrial PKA activity may play a role in the phosphorylation and transactivation of mitochondrial ERs and CREB. We will further characterize mitochondrial ER, PKA, and CREB activity in mouse models of HD. 3) To develop therapeutic approaches to target mitochondrial ERs and CREB in vitro and in vivo in transgenic and Knock-in HD mice expressing short segment and full length mutant huntingtin. We will determine whether specific estrogen receptor modulators (SERMs) augment mitochondrial PKA activity and mitochondrial ER and CREB phosphorylation to induce mitochondrial gene transcription that influences neuronal survival. These studies will provide novel mechanisms for preventing mitochondrial transcriptional dysfunction and help in the design of applicable compounds that modulate mitochondrial function.